Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20111
標題: Gefitinib誘發黑色素生成之分子機轉
The molecular mechanism of Gefitinib-induced Melanogenesis in melanoma cell
作者: 蔡佳容
Tsai, Jia-Rong
關鍵字: tyrosinase;黑色素
出版社: 生物醫學研究所
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摘要: 
肺癌是全球致死率最高的癌症,主要分成兩大類:一為非小細胞肺癌,其發生率約為85%;另一類為小細胞肺癌約佔15%。以目前常用之方法治療肺癌病人,其五年的存活率仍僅為14%。因此,研發安全有效的肺癌治療策略實為當務之急。Gefitinib為一種合成小分子quinazoline的衍生物,可以選擇性的抑制癌細胞上過多的上皮細胞生長因子受体 (epidermal growth factor receptor)酪胺酸激酶 (tyrosine kinase)的活性,目前已應用於治療癌症病人。臨床上顯示Gefitinib可有效應用於台灣肺癌末期病人,但是有些病人在服用Gefitinib後,皮膚產生了黑色素暗沈的現象,其確切機轉仍無文獻報導。本篇論文主要利用培養的人類黑色素腫瘤細胞株 (A2058)與小鼠黑色素腫瘤細胞株 (B16F1) ,探討Gefitinib引起皮膚色素暗沈的分子機轉。結果發現處理Gefitinib可使黑色素腫瘤細胞株內酪胺酸酶的活性及黑色素的生成明顯的增加,有劑量和時間的依存效應。我們發現Gefitinib所引起黑色素生成的機轉,主要在於調控黑色素生成的分子,如酪胺酸酶 (Tyrosinase)、TRP1 (Tyrosinase related protein 1)和 TRP2表現量增加,同時伴隨著抑制黑色素生成的分子如磷酸化ERK及AKT的減少。綜合以上的結果,本論文首度證明Gefitinib引起黑色素生成的機轉,可能是透過調控ERK及AKT失活性的路徑造成黑色素生成分子的表現增加。

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of all types of lung cancer, while small cell lung cancer (SCLC) accounts for the rest 15%. In spite of continuous invention of treatments, the overall five-year survival rate remains low. Novel therapeutic strategies to improve efficacy in accord with safety are urgently needed. Gefitinib is a quinazoline derivative that selectively inhibits epithelial growth factor receptor (EGFR) tyrosine kinase activity and is under clinical use in cancer patients. Clinically, gefitinib has good antitumor activity and tolerability in Taiwan patients with advanced NSCLC. In some of patients, the unique side effect of gefitinib is skin hyperpigmentation. However, the molecular mechanism of gefitinib-mediated melanogenesis effect is not fully understood. In this study, the effect of gefitinib on melanogenesis was examined in murine B16F1 and human A2058 melanoma cells. The tyrosinase activity was apparently elevated in cells treated with gefitinib. Moreover, treatment with gefitinib increased the melanin content of melanoma cells in a dose- and time-dependent manner. In studies of the mechanisms underlying such induction, we found that the molecular promoting pigment production such as tyrosinase, tyrosinase-related protein 1 and 2 were increasingly expressed in gefitinib-treated melanoma cells, which was accompanied by the inactivation of Akt and ERK, two factors documented to exert inhibitory effect on melanogenesis. Taken together, our findings propose that gefitinib induces melanin synthesis through the inactivation of negative regulators of pigment generation and subsequent elevation of melanin-producing enzymes.
URI: http://hdl.handle.net/11455/20111
其他識別: U0005-2708200711051900
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